@article{4042810e86064857b5e92d3f16ac846d,
title = "Deciphering cellular transcriptional alterations in Alzheimer's disease brains",
abstract = "Large-scale brain bulk-RNAseq studies identified molecular pathways implicated in Alzheimer's disease (AD), however these findings can be confounded by cellular composition changes in bulk-tissue. To identify cell intrinsic gene expression alterations of individual cell types, we designed a bioinformatics pipeline and analyzed three AD and control bulk-RNAseq datasets of temporal and dorsolateral prefrontal cortex from 685 brain samples. We detected cell-proportion changes in AD brains that are robustly replicable across the three independently assessed cohorts. We applied three different algorithms including our in-house algorithm to identify cell intrinsic differentially expressed genes in individual cell types (CI-DEGs). We assessed the performance of all algorithms by comparison to single nucleus RNAseq data. We identified consensus CI-DEGs that are common to multiple brain regions. Despite significant overlap between consensus CI-DEGs and bulk-DEGs, many CI-DEGs were absent from bulk-DEGs. Consensus CI-DEGs and their enriched GO terms include genes and pathways previously implicated in AD or neurodegeneration, as well as novel ones. We demonstrated that the detection of CI-DEGs through computational deconvolution methods is promising and highlight remaining challenges. These findings provide novel insights into cell-intrinsic transcriptional changes of individual cell types in AD and may refine discovery and modeling of molecular targets that drive this complex disease.",
keywords = "Alzheimer's disease, Bioinformatics, Cell-specific gene expression, Deconvolution, Gene expression, Neurodegeneration, RNA sequencing, Transcriptome",
author = "Xue Wang and Mariet Allen and Shaoyu Li and Quicksall, {Zachary S.} and Patel, {Tulsi A.} and Carnwath, {Troy P.} and Reddy, {Joseph S.} and Carrasquillo, {Minerva M.} and Lincoln, {Sarah J.} and Nguyen, {Thuy T.} and Malphrus, {Kimberly G.} and Dickson, {Dennis W.} and Crook, {Julia E.} and Asmann, {Yan W.} and Nil{\"u}fer Ertekin-Taner",
note = "Funding Information: We thank the patients and their families for their participation, without them these studies would not have been possible. The Mayo RNAseq study data was led by Dr. Nil{\"u}fer Ertekin-Taner, Mayo Clinic, Jacksonville, FL as part of the multi-PI U01 AG046139 (MPIs Golde, Ertekin-Taner, Younkin, Price) using samples from The Mayo Clinic Brain Bank. Data collection was supported through funding by NIA grants P50 AG016574, R01 AG032990, U01 AG046139, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216, R01 AG003949, NINDS grant R01 NS080820, CurePSP Foundation, and support from Mayo Foundation. This study was in part funded by NIH RF1 AG051504 and R01 AG061796 (NET). We thank the Mayo Clinic Advanced Genomic Technology Center staff and bioinformatics core facility for all gene expression measurements. XW thanks Dr. E. Aubrey Thompson for text editing and Jeremy Burgess for provide insightful inputs. XW was funded in part by a pilot grant from the Mayo Clinic ADRC (P50 AG016574). The results published here are in whole or in part based on data obtained from the AMP-AD Knowledge Portal (https://adknowledgeportal.synapse.org). Study data were provided by the Rush Alzheimer{\textquoteright}s Disease Center, Rush University Medical Center, Chicago. Data collection was supported through funding by NIA grants P30AG10161 (ROS), R01AG15819 (ROSMAP; genomics and RNAseq), R01AG17917 (MAP), R01AG30146, R01AG36042 (5hC methylation, ATACseq), RC2AG036547 (H3K9Ac), R01AG36836 (RNAseq), R01AG48015 (monocyte RNAseq) RF1AG57473 (single nucleus RNAseq), U01AG32984 (genomic and whole exome sequencing), U01AG46152 (ROSMAP AMP-AD, targeted proteomics), U01AG46161(TMT proteomics), U01AG61356 (whole genome sequencing, targeted proteomics, ROSMAP AMP-AD), the Illinois Department of Public Health (ROSMAP), and the Translational Genomics Research Institute (genomic). The results published here are in whole or in part based on data obtained from the AMP-AD Knowledge Portal (https://adknowledgeportal.synapse.org/ ). These data were generated from postmortem brain tissue collected through the Mount Sinai VA Medical Center Brain Bank and were provided by Dr. Eric Schadt from Mount Sinai School of Medicine. Funding Information: This study was funded by the following studies: NIH/NIA U01 AG046139, RF1 AG051504 and R01 AG061796 (N.E-T.); P50 AG016574 Pilot grant (XW). Publisher Copyright: {\textcopyright} 2020 The Author(s).",
year = "2020",
month = jul,
day = "13",
doi = "10.1186/s13024-020-00392-6",
language = "English (US)",
volume = "15",
journal = "Molecular neurodegeneration",
issn = "1750-1326",
publisher = "BioMed Central",
number = "1",
}